WO2022030622A1

WO2022030622A1 - Method for producing compound

Info

Publication number: WO2022030622A1
Application number: PCT/JP2021/029343
Authority: WO
Inventors: 僚張替; 千絵美小島; 慎悟今野; 徹山崎
Original assignee: 株式会社クレハ
Priority date: 2020-08-06
Filing date: 2021-08-06
Publication date: 2022-02-10
Also published as: US20230271929A1; JP7427096B2; JPWO2022030622A1; CN116171273B; EP4194445A4; CN116171273A; EP4194445A1

Abstract

The present invention provides a method which can produce an intermediate of an azole derivative at lower cost than an existing production method. The method is for producing a compound represented by general formula (IV) and includes a step in which a compound represented by general formula (II) is converted into the compound represented by general formula (IV) in the presence of an inorganic base using both (a) dimethyl sulfide and/or dimethyl sulfoxide and (b) a methyl-LG (wherein LG is a nucleophilically replaceable leaving group and is selected from among halogen groups, alkoxysulfonyloxy groups, aryloxysulfonyloxy groups, alkylsulfonyloxy groups, haloalkylsulfonyloxy groups, and arylsulfonyloxy groups).

Description

Method for producing compound

The present invention relates to a method for producing a compound.

Azole derivatives are useful as agricultural and horticultural agents that show a high control effect. Then, in order to produce an azole derivative, a method for producing an intermediate of the azole derivative is being studied. For example, Patent Document 1 discloses a method for producing methyl 2- (2-chloro-4- (4-chlorophenoxy) phenyl) -2-oxoacetic acid, which is an intermediate of an azole derivative.

International Publication No. 2019/093522

In the method for producing an intermediate compound of an azole derivative described in Patent Document 1, a step of performing oxylanation using trimethylsulfoxonium bromide (TMSOB) and a step of converting a ketone group into a ketoester group using iodine or iodomethane. The process of replacement is disclosed. However, since TMSOB, iodine, and iodomethane are expensive, there is a problem that the production cost of an intermediate of an azole derivative increases. Therefore, there is a demand for a method capable of producing an intermediate of an azole derivative at a lower cost.

The present invention has been made in view of the above problems, and one aspect of the present invention is to realize a method capable of producing an intermediate of an azole derivative at a lower cost than an existing production method. do.

In order to solve the above-mentioned problems, the production method according to one aspect of the present invention is a production method for a compound represented by the general formula (IV).

[In formula (IV), R ¹ is _a C1-C6 _- alkyl group;
X ¹ is a halogen group, _a C1- _C4 -haloalkyl group or _a C1- _C4 -haloalkoxy group;
X ² is a halogen group, _a C1- _C4 -haloalkyl group or _a C1- _C4 -haloalkoxy group;
n is 1, 2 or 3]
In the coexistence of inorganic bases
(A) At least one of dimethyl sulfide and dimethyl sulfoxide, and (b) Methyl-LG (where LG is a nucleophilically replaceable desorbing group, a halogen group, an alkoxysulfonyloxy group, an aryloxysulfonyloxy). Group, alkylsulfonyloxy group, haloalkylsulfonyloxy group, and arylsulfonyloxy group)
The production method comprising the step of converting the compound represented by the general formula (II) into the compound represented by the general formula (IV) using the above:

[In formula (II), R ¹ , X ¹ , X ² , and n are the same as R ¹ , X ¹ , X ² , and n in formula (IV)].

According to one aspect of the present invention, the intermediate of the azole derivative can be produced at a lower cost than the existing production method.

The X-ray diffraction pattern of the triazole-1-yl body (A) is shown. intensity indicates the X-ray diffraction intensity, and Angle indicates the diffraction angle (2θ). The X-ray diffraction pattern of the triazole-4-yl body (B) is shown. intensity indicates the X-ray diffraction intensity, and Angle indicates the diffraction angle (2θ). The X-ray diffraction pattern of the triazole-1-yl: triazole-4-yl = 95: 5 mixture (C) synthesized in this example is shown. intensity indicates the X-ray diffraction intensity, and Angle indicates the diffraction angle (2θ).

Hereinafter, a suitable mode for carrying out the present invention will be described. It should be noted that the embodiments described below show an example of a typical embodiment of the present invention, and the scope of the present invention is not narrowly interpreted by this.

[1. Method for producing a compound represented by the general formula (IV)]
A method for producing a compound represented by the general formula (IV) according to one aspect of the present invention (hereinafter referred to as "oxylan derivative (IV)") (hereinafter referred to as "production method 1") will be described:

[In formula (IV), R ¹ is _a C1-C6 _- alkyl group;
X ¹ is a halogen group, _a C1- _C4 -haloalkyl group or _a C1- _C4 -haloalkoxy group;
X ² is a halogen group, _a C1- _C4 -haloalkyl group or _a C1- _C4 -haloalkoxy group;
n is 1, 2 or 3].

The C1 _- C6 _- alkyl group is a linear or branched alkyl group having 1 to 6 carbon atoms, and is, for example, a methyl group, an ethyl group, a 1-methylethyl group, or a 1,1-dimethyl group. Ethyl group, propyl group, 1-methylpropyl group, 2-methylpropyl group, 1,1-dimethylpropyl group, 2,2-dimethylpropyl group, 1-ethylpropyl group, butyl group, 1-methylbutyl group, 2- Methylbutyl group, 3-methylbutyl group, 3,3-dimethylbutyl group, 2,2-dimethylbutyl group, 1,1-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group, pentyl group, 1-methylpentyl group , 2-Methylpentyl group, 3-methylpentyl group or 4-methylpentyl group.

Examples of the halogen group include a chlorine group, a bromine group, an iodine group or a fluorine group.

In the C1- _C4 _- haloalkyl group, one or two or more halogen atoms are substituted at substitutable positions of the C1- _C4 _- alkyl group, and when the number of substituted halogen groups is two or more, the halogen is used. The groups may be the same or different. The C1- _C4 _- alkyl group is a linear or branched-chain alkyl group having 1 to 4 carbon atoms.

The C1- _C4 _- alkyl group is a linear or branched alkyl group having 1 to 4 carbon atoms, and examples thereof include a methyl group, an ethyl group, a propyl group and a butyl group. The halogen group is as described above. Examples of the C1- _C4 _- haloalkyl group include a chloromethyl group, a 2-chloroethyl group, a 2,3-dichloropropyl group, a bromomethyl group, a chlorodifluoromethyl group, a trifluoromethyl group, and 3,3,3-. Examples include a trifluoropropyl group.

In the C1- _C4 _- haloalkoxy group, _one or two or more halogen atoms are substituted at substitutable positions of the C1- _C4 -alkoxy group, and when the number of substituted halogen groups is two or more, the halogen atom is substituted. The halogen groups may be the same or different. The C1- _C4 _- alkoxy group is a linear or branched-chain alkoxy group having 1 to 4 carbon atoms.

The C1- _C4 _- alkoxy group is a linear or branched alkoxy group having 1 to 4 carbon atoms, and is, for example, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, or a 1-methylpropoxy group. , 2-Methylpropoxy group, butoxy group, 1,1-dimethylethoxy group and the like.

The production method 1 of this embodiment is a step of converting a compound represented by the general formula (II) (hereinafter referred to as “ketoester derivative (II)”) into an oxirane derivative (IV) according to the following scheme 1. (Referred to as "step 1"). In addition, R ¹ , X ¹ , X ² , and n in the following scheme 1 correspond to R ¹ , X ¹ , X ² , and n in the general formula (IV).

(Step 1)
In the manufacturing method 1 of this embodiment, the step 1 is
In the coexistence of inorganic bases
(A) At least one of dimethyl sulfide and dimethyl sulfoxide, and (b) Methyl-LG (where LG is a nucleophilically replaceable desorbing group, a halogen group, an alkoxysulfonyloxy group, an aryloxysulfonyloxy). Group, alkylsulfonyloxy group, haloalkylsulfonyloxy group, and arylsulfonyloxy group)
Is a step of converting the ketoester derivative (II) into the oxylan derivative (IV) using the above.

[In formula (II), R ¹ , X ¹ , X ² , and n are identical to R ¹ , X ¹ , X ² , and n in formula (IV)].

In step 1, oxylanation is performed while preparing a sulfonium salt in the reaction system using at least one of dimethyl sulfide and dimethyl sulfoxide and methyl-LG. That is, the preparation of the sulfonium salt and the oxyranization reaction are carried out at the same time.

The inorganic base is added from the viewpoint of advancing the reaction of step 1. Examples of the inorganic base used in step 1 include sodium hydride, cesium carbonate, potassium phosphate, potassium carbonate and the like, and potassium carbonate is preferable.

LG is a leaving group selected from a nucleophilically replaceable leaving group, for example, a halogen group, an alkoxysulfonyloxy group, an aryloxysulfonyloxy group, an alkylsulfonyloxy group, a haloalkylsulfonyloxy group, and an arylsulfonyloxy group. It shows a group, preferably an alkoxysulfonyloxy group.

The amount of the inorganic base coexisting in the reaction system in step 1 is 1.0 to 10.0 equivalents (eq.) With respect to 1 equivalent (eq.) Of the ketoester derivative (II) from the viewpoint of advancing the reaction of step 1. ) Is preferable.

The amount of the above-mentioned "(a) at least one of dimethyl sulfide and dimethyl sulfoxide" (referred to as "required amount of reaction") added to the reaction system in step 1 is the ketoester derivative (II) 1 from the viewpoint of carrying out the reaction in just proportion. It is preferably 1.0 to 10.0 equivalents (eq.) With respect to the equivalent (eq.).

The amount of the "(b) methyl-LG" added to the reaction system in step 1 (referred to as "required amount of reaction") is 1 equivalent (eq.) Of the ketoester derivative (II) from the viewpoint of carrying out the reaction in just proportion. On the other hand, it is preferably 1.0 to 10.0 equivalents (eq.).

Step 1 proceeds in an organic solvent. As the organic solvent, a solvent in which the reaction of step 1 proceeds is appropriately selected, and examples thereof include dichloroethane and the like. The reaction of step 1 can be carried out, for example, while heating, refluxing and stirring in an oil bath. At this time, the oil bath temperature may be, for example, 85 to 100 ° C. so that the internal temperature is 80 to 90 ° C.

In the production method 1 of this embodiment, in step 1, it is preferable to add the reaction required amounts of the above (a) and (b) in divided portions. The divided addition in step 1 means that the required reaction amounts of (a) and (b) are added in one or more divided portions. A person skilled in the art can appropriately set an appropriate timing and number of additions from the second time onward in consideration of reaction conditions and the like. For example, the second divided addition may be performed before the activity of the reagent added the first time is lost. By the divided addition of (a) and (b), the reaction of (a) and (b) required for the reaction of step 1 is compared with the case where the (a) and (b) are added all at once without the divided addition. It has the effect of reducing the amount of reagents used. It is considered that this is because the reaction is efficiently carried out by the divided addition of (a) and (b) as compared with the case of adding (a) and (b) all at once.

Since it is sufficient that all the required reaction amounts described above can be added to the reaction system, the addition amount for each addition (referred to as "divided addition amount") is not particularly limited. The amount of the divided addition can be appropriately adjusted according to the number of times of the divided addition. Further, each divided addition amount (for example, the divided addition amount of the first and second divided additions when the required reaction amount is divided into two portions) may be the same or different.

The above (a) may be at least one of dimethyl sulfide and dimethyl sulfoxide, but both dimethyl sulfide and dimethyl sulfoxide are preferable. In (a), the addition of dimethyl sulfide and dimethyl sulfoxide in combination has the effect of not only reducing the amount of reagent used but also improving the yield, as compared with the case where only dimethyl sulfoxide is added. ..

In the production method 1 of this embodiment, instead of TMSOB, at least one of dimethyl sulfide and dimethyl sulfoxide, which are relatively easily available, and methyl-LG are used for oxylanation, so that it is not necessary to separately prepare TMSOB. By implementing the manufacturing method 1 of this embodiment, the construction cost of the plant required for manufacturing the TMSOB, the labor cost at the time of manufacturing, the utility cost, etc. are not required, and the practitioner of the manufacturing method 1 of the present embodiment manufactures the TMSOB. It is possible to enjoy manufacturing merits such as shortening of the batch cycle time required for. Further, since the practitioner of the production method 1 of this embodiment handles DMSO under basic conditions, it is possible to enjoy the merit of high safety in production.

The oxylane derivative (IV) produced by the production method 1 of this embodiment is one of the intermediates of the compound represented by the general formula (I) described later (hereinafter referred to as “azole derivative (I)”). According to the production method 1 of this embodiment, the oxylan derivative (IV) can be produced at low cost without using expensive TMSOB, iodine, and iodomethane, so that the azole derivative (I) can be produced at low cost.

[In formula (I), R ¹ , X ¹ , X ² , and n are the same as R ¹ , X ¹ , X ² , and n in the general formula (IV)].

[2. Method for producing ketoester derivative (II)]
The production method 1 of this embodiment may include the production method of the ketoester derivative (II) of this embodiment (hereinafter referred to as “production method 2”) before the step 1.

Hereinafter, the production method 2 of this embodiment is a step of converting a compound represented by the general formula (III) (hereinafter referred to as “methyl ketone derivative (III)”) into a ketoester derivative (II) according to the following scheme 2. (Hereinafter referred to as "step 2") is included. In addition, R ¹ , X ¹ , X ² , and n in the following scheme 2 correspond to R ¹ , X ¹ , X ² , and n in the general formula (IV).

(Step 2)
In the production method 2 of this embodiment, in step 2, bromine is allowed to act on the methyl ketone derivative (III) while heating the reaction system in a solvent containing dimethyl sulfoxide, and then R1 ^- OH (where ^R1 is referred to as R1). It is the same as R ¹ in the general formula (IV)) to produce a ketoester derivative (II).

[In formula (III), X ¹ , X ² , and n are the same as X ¹ , X ² , and n in formula (IV)].

In step 2, the synthesis of ketocarboxylic acid using bromine and dimethyl sulfoxide and the esterification using R1 ^- OH are continuously carried out. By using bromine in the synthesis reaction of ketocarboxylic acid, the ketoester derivative (II) can be produced at low cost and the yield is high as compared with the case where iodine is used as in Patent Document 1. Further, since R1 ^- OH is used as the esterification reagent used in the esterification reaction, the ketoester derivative (II) can be produced at a lower cost as compared with the case where iodomethane is used as in Patent Document 1.

The amount of dimethyl sulfoxide added to the reaction system in step 2 is 2.0 to 10.0 equivalents (eq.) With respect to 1 equivalent (eq.) Of the methylketone derivative (III) from the viewpoint of carrying out the reaction in just proportion. Is preferable.

The amount of bromine added to the reaction system in step 2 is 0.5 to 3.0 equivalents (eq.) With respect to 1 equivalent (eq.) Of the methylketone derivative (III) from the viewpoint of carrying out the reaction in just proportion. It is preferable to have.

The reaction temperature of the ketocarboxylic acid synthesis reaction in step 2 is preferably 60 to 85 ° C, more preferably 70 ° C, from the viewpoint of preferably carrying out the reaction. For example, the synthetic reaction of ketocarboxylic acid in step 2 can be carried out while stirring and heating so that the internal temperature becomes the above temperature in an oil bath. Further, the esterification reaction in step 2 can be carried out, for example, while heating and refluxing in an oil bath. At this time, the oil bath temperature may be 60 to 80 ° C. so that the internal temperature is preferably 55 to 65 ° C., more preferably 65 ° C.

Step 2 proceeds in an organic solvent. As the organic solvent, a solvent in which the reaction of step 2 proceeds is appropriately selected, and examples thereof include dichloroethane and the like.

In the production method 2 according to another aspect of the present invention, in step 2, the reaction system to which bromine is added is heated in a solvent containing dimethyl sulfoxide, and then the methyl ketone derivative (III) is added to the methyl ketone derivative (III). Can be reacted with bromine and then with ^{R1-OH (where R 1 is the same as R 1} ⁱⁿ ^the general formula (IV)) to produce the ketoester derivative (II). good.

When the methyl ketone derivative (III) is added after heating the reaction system to which bromine has been added, the heating temperature of the reaction system before the addition of the methyl ketone derivative (III) is preferably an internal temperature of 60 to 75 ° C., 65. More preferably, it is ° C. The reaction temperature of the reaction system after the addition of the methyl ketone derivative (III) is preferably 65 to 80 ° C, more preferably 70 ° C. By adding the methyl ketone derivative (III) after heating the reaction system to which bromine is added, the heat generation generated during the synthetic reaction of ketocarboxylic acid can be suppressed, so that the step 2 can proceed more safely.

Further, in the production method 2 according to another aspect, the step 2 is preferably carried out in the coexistence of at least one compound selected from the group consisting of urea, adipic acid dihydrazide and dibutylhydroxytoluene. It is more preferable to carry out in coexistence. In step 2, white deposits are generated in the reaction vessel by using bromine. Although this white deposit is not contained in the final product of step 2, it causes clogging of the reaction vessel, so it is necessary to remove the white deposit in the reaction vessel each time. However, by carrying out the reaction of step 2 in the coexistence of the compound, it is possible to suppress the generation of white deposits adhering to the inside of the reaction vessel in step 2. As a result, the practitioner can enjoy the merit that the production efficiency is improved because the treatment for removing the white deposits in the reaction vessel becomes unnecessary. Since the effect of suppressing the generation of white deposits is high, the compound coexisting in the reaction system in step 2 is preferably urea.

The amount of at least one compound selected from the group consisting of urea, adipic acid dihydrazide and dibutylhydroxytoluene coexisting in the reaction system in step 2 is the amount of the methyl ketone derivative (III) 1 from the viewpoint of suppressing the generation of white deposits. It is preferably 0.1 to 2.0 equivalents (eq.) With respect to the equivalent (eq.).

[3. Method for Producing Azole Derivative (I)]
The method for producing the azole derivative (I) of this embodiment (hereinafter referred to as "production method 3") will be described. The production method 3 of this embodiment includes the above-mentioned production method of the oxylan derivative (IV) of the present embodiment in order to produce the oxylan derivative (IV) which is an intermediate of the azole derivative (I), and is obtained by the production method. A step of converting the obtained oxylan derivative (IV) into an azole derivative (I) according to the following scheme 3 (hereinafter referred to as “step 3”) is included. With such a configuration, the oxylan derivative (IV) can be produced at low cost, so that the azole derivative (I) can be produced at low cost.

Since the method for producing the oxylan derivative (IV) is as described above, only step 3 will be described here. In addition, R ¹ , X ¹ , X ² , and n in the following scheme 3 correspond to R ¹ , X ¹ , X ² , and n in the general formula (IV).

In the production method 3 of this embodiment, in step 3, the oxylan derivative (IV) produced by the production method 1 is used as an azole derivative (I) using 1,2,4-triazole in the presence of an inorganic base. Convert to.

In step 3, 1,2,4-triazole and an inorganic base are used, and a salt of 1,2,4-triazole and the inorganic base (for example, when potassium carbonate is used as the inorganic base) in the reaction system. , 1,2,4-Triazole potassium salt) is azoled. As a result, the practitioner does not need to prepare a salt of 1,2,4-triazole and an inorganic base in advance, and thus can enjoy the merit of improving the production efficiency.

The inorganic base used in step 3 is as illustrated in the description of step 1. The inorganic base used in step 3 may be the same as or different from the inorganic base used in step 1.

The amount of the inorganic base coexisting in the reaction system in step 3 is 0.1 to 3.0 equivalents (eq.) With respect to 1 equivalent (eq.) Of the oxylane derivative (IV) from the viewpoint of advancing the reaction in step 3. ) Is preferable.

The amount of 1,2,4-triazole added to the reaction system in step 3 is 1.0 to 1 equivalent (eq.) Of the oxylan derivative (IV) from the viewpoint of carrying out the reaction of step 3 in just proportion. It is preferably 3.0 equivalents (eq.).

Step 3 proceeds in an organic solvent. As the organic solvent, a solvent in which the reaction of step 3 proceeds is appropriately selected, and examples thereof include N, N-dimethylformamide, N, N-dimethylacetamide and the like. The reaction of step 3 can be carried out, for example, with stirring at room temperature or while heating and stirring in an oil bath. The reaction temperature at this time is, for example, an internal temperature of 40 to 120 ° C.

The method for converting the oxylan derivative (IV) to the azole derivative (I) is not limited to the above-mentioned method, and a known method (for example, the method disclosed in Patent Document 1) can also be used. be. Therefore, the production method 3 according to another aspect of the present invention includes the above-mentioned method for producing the oxylan derivative (IV) of the present embodiment, and the oxylan derivative (IV) obtained by the production method is used as a known method ( For example, it may be a method of converting to an azole derivative (I) according to the method disclosed in Patent Document 1).

The present invention is not limited to the above-described embodiments, and various modifications can be made within the scope of the claims, and the embodiments obtained by appropriately combining the technical means disclosed in the different embodiments. Is also included in the technical scope of the present invention.

〔summary〕
The production method according to the first aspect is a method for producing a compound represented by the general formula (IV), in which (a) at least one of dimethyl sulfide and dimethylsulfoxide, and (b) in the presence of an inorganic base. Methyl-LG (where LG is a nucleophilically replaceable desorbing group, a halogen group, an alkoxysulfonyloxy group, an aryloxysulfonyloxy group, an alkylsulfonyloxy group, a haloalkylsulfonyloxy group, and an arylsulfonyloxy group. (Selected from the group) is used to convert the compound represented by the general formula (II) into the compound represented by the general formula (IV). With such a configuration, the oxylan derivative (IV) can be produced without using costly TMSOB.

In the production method according to the second aspect, in the step 1 of converting into the compound represented by the general formula (IV) in the first aspect, the reaction required amounts of the above (a) and the above (b) are divided and added. It is preferable to do so. Since the reaction is efficiently carried out by the divided addition of (a) and (b), the amount of the reagent used in (a) and (b) can be reduced.

In the production method according to the third aspect, in the first or second aspect, the above (a) is preferably both dimethyl sulfide and dimethyl sulfoxide. In (a), the addition of dimethyl sulfide has the effect of reducing the amount of reagent used in (a).

The production method according to the fourth aspect further comprises, in any one of the first to third aspects, the step 2 of converting the compound represented by the general formula (III) into the compound represented by the general formula (II). In the step 2, bromine is allowed to act on the compound represented by the general formula (III) while heating the reaction system in a solvent containing dimethyl sulfoxide, and then R ¹ −OH (where R ¹ is represented by the formula (where R 1 is)). It may be configured to produce the compound represented by the general formula (II) by allowing the action (which is the same as R ¹ in IV). With such a configuration, the ketoester derivative (II) can be produced without using costly iodine or iodomethane.

In the production method according to the fifth aspect, in the step 2 of converting to the compound represented by the general formula (II) in the present aspect 4, the reaction system to which bromine is added is heated in a solvent containing dimethyl sulfoxide and then generally used. The compound represented by the formula (III) is added to cause bromine to act on the compound represented by the general formula (III), and then R ¹ -OH (where R ¹ is R in the formula (IV)). It is preferable to carry out the same reaction as ¹ ) to produce the compound represented by the general formula (II). By adding the methyl ketone derivative (III) after heating the reaction system, heat generation can be suppressed, so that step 2 can proceed safely.

In the production method according to the sixth aspect, in the fourth or fifth aspect, the step 2 for converting to the compound represented by the general formula (II) is selected from the group consisting of urea, adipic acid dihydrazide and dibutylhydroxytoluene. It is preferable to carry out in the coexistence of at least one kind. With such a configuration, it is possible to suppress the generation of white deposits adhering to the inside of the reaction vessel in step 2.

The production method according to this aspect 7 is a method for producing a compound represented by the general formula (I), and is a method for producing a compound represented by the general formula (IV) according to any one of the present aspects 1 to 6. The compound represented by the general formula (IV) obtained by the production method is represented by the general formula (I) using 1,2,4-triazole in the presence of an inorganic base. It is a configuration including a step 3 for converting into a compound to be made. With such a configuration, the production cost of the intermediate of the azole derivative (I) can be reduced, so that the production cost of the azole derivative (I) can be reduced.

Hereinafter, the present invention will be specifically described with reference to manufacturing examples. The present invention is not limited to the following production examples as long as the gist of the present invention is not exceeded.

<Synthesis example 1>
Methyl 2- (2-chloro-4- (4-chlorophenoxy) phenyl) -2-oxylancarboxylate (Synthesis Example 1-1)
Add 0.98 g (3.0 mmol) of 2- (2-chloro-4- (4-chlorophenoxy) phenyl) -2-oxoacetic acid methyl 0.98 g (3.0 mmol) and 4.5 mL of dichloroethane to the flask, and then add 2.24 g (16) of potassium carbonate. .2 mmol), 1.54 mL (16.2 mmol) of dimethyl sulfate, and 0.58 mL (8.1 mmol) of dimethyl sulfoxide were added, and the mixture was heated under reflux in an oil bath at 95 ° C. and stirred. Two hours after the start of the reaction, water was added, the mixture was extracted twice with dichloroethane, and this was washed once with water. After drying over anhydrous sodium sulfate, the solvent was distilled off to obtain 1.06 g of a crude yellow liquid.

The title compound in this yellow liquid crude product was quantified by NMR. As a result, the NMR quantitative yield of the title compound was 61%.

(Synthesis Example 1-2)
Crude 2- (2-chloro-4- (4-chlorophenoxy) phenyl) -2-oxomethyl acetate 12.90 g (purity 76%, 30 mmol), potassium carbonate 14.95 g (108 mmol), and 60 mL dichloroethane in a flask. After the addition, 3.84 mL (54 mmol) of dimethyl sulfoxide and 10.26 mL (108 mmol) of dimethyl sulfate were added in portions. The reaction was carried out under heating and reflux using an oil bath at 95 ° C. After 7.5 hours from the start of the reaction, water was added to separate the liquids, the aqueous layer was re-extracted once with dichloroethane, and then the organic layers were combined and washed twice. After drying over anhydrous sodium sulfate, the solvent was distilled off to obtain 13.07 g of a crude orange liquid.

The title compound in this orange liquid crude product was quantified by gas chromatography (GC quantification). As a result, the GC quantitative yield of the title compound was 91%.

(Synthesis Example 1-3)
Crude 2- (2-chloro-4- (4-chlorophenoxy) phenyl) -2-oxomethyl acetate 17.18 g (purity 76%, 40 mmol), potassium carbonate 13.27 g (96 mmol), dimethyl sulfide 1.8 mL ( 24 mmol) and 60 mL of dichloroethane were added to the flask, followed by addition of 3.4 mL (48 mmol) of dimethyl sulfoxide and 7.1 mL (96 mmol) of dimethyl sulfate in portions. The reaction was carried out under heating and reflux using an oil bath at 95 ° C. After 5 hours from the start of the reaction, water was added to separate the liquids, and the organic layer was washed twice. After drying over anhydrous sodium sulfate, the solvent was distilled off to obtain 17.50 g of a crude orange liquid.

The title compound in the orange liquid crude product was quantified by gas chromatography (GC quantification). As a result, the GC quantitative yield of the title compound was 97%.

(Synthesis Example 1-4)
2- (2-Chloro-4- (4-chlorophenoxy) phenyl) -2-oxomethyl acetate 0.98 g (3.0 mmol), potassium phosphate 3.82 g (18.0 mmol), and dichloroethane 6.0 mL. After addition to the flask, 0.85 mL (9.0 mmol) of dimethyl sulfate and 0.32 mL (4.5 mmol) of dimethyl sulfoxide were added in portions. The reaction was carried out in an oil bath at 95 ° C. under heating and reflux. After 7 hours from the start of the reaction, water was added, the mixture was extracted twice with dichloroethane, and this was washed once with water. After drying over anhydrous sodium sulfate, the solvent was distilled off to obtain 1.16 g of a crude yellow liquid.

The title compound in this yellow liquid crude product was quantified by NMR. As a result, the NMR quantitative yield of the title compound was 76%.

<Synthesis example 2>
Synthesis of 2- (2-chloro-4- (4-chlorophenoxy) phenyl) -2-oxomethyl acetate (Synthesis Example 2-1)
Add 28.11 g (0.10 mol) of 2'-chloro-4'-(4-chlorophenoxy) acetophenone, 50 mL of dimethyl sulfoxide, and 45 mL of dichloroethane to a flask, dissolve, cool in an ice bath, and then 19.32 g of bromine (. 0.12 mol) was added with a dropping funnel, washed with 5 mL of dichloroethane, and heated and stirred in an oil bath so that the internal temperature became 70 ° C. After 1 hour, the low boiling material was distilled off, 50 mL of toluene and 50 mL of methanol were added, and the mixture was heated under reflux. After 1 hour, 50 mL of toluene was added to separate the lower layer of the solution and the lower layer was re-extracted once with toluene. The upper layer and the re-extracted toluene were combined and washed once with saturated brine, washed once with water, and washed once with saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off to obtain 30.83 g of a crude orange liquid.

The title compound in this orange liquid crude product was quantified by gas chromatography (GC quantification). As a result, the GC quantitative yield of the title compound was 83%.

(Synthesis Example 2-2)
After adding 100 mL of dichloroethane to the flask, 38.36 g (0.24 mol) of bromine was added with a dropping funnel and stirred. After cooling the reaction vessel in a water bath, 28.4 mL of dimethyl sulfoxide was added with a dropping funnel. After heating in an oil bath to an internal temperature of 70 ° C., a solution of 56.23 g (0.20 mol) of 2'-chloro-4'-(4-chlorophenoxy) acetophenone in dimethyl sulfoxide 85.2 mL is added with a dropping funnel. added. One hour after the completion of the dropping, 7.1 mL of dimethyl sulfoxide was added. After another 1 hour, the low boiling material was distilled off, 100 mL of toluene and 100 mL of methanol were added, and the mixture was heated under reflux. After 2 hours, 100 mL of toluene was added to separate the lower layer of the solution and the lower layer was re-extracted once with toluene. The upper layer and the re-extracted toluene were combined and washed once with saturated layered water and washed twice. The solvent was distilled off to obtain 59.29 g of a crude orange liquid.

The title compound in this orange liquid crude product was quantified by gas chromatography (GC quantification). As a result, the GC quantitative yield of the title compound was 77%.

(Synthesis Example 2-3)
After adding 18.01 g (0.30 mol) of urea and 468 mL of dichloroethane to the flask, 191.80 g (1.20 mol) of bromine was added with a dropping funnel and stirred. After cooling the reaction vessel in a water bath, a mixed solution of 156.26 g (2.00 mol) of dimethyl sulfoxide and 25 mL of dichloroethane was added with a dropping funnel. After gradually heating in an oil bath while observing the internal temperature until the internal temperature reaches 70 ° C, dimethyl sulfoxide 468 of 2'-chloro-4'-(4-chlorophenoxy) acetophenone 283.11 g (1.00 mol) A .77 g (6.00 mol) solution was added with a dropping funnel. One hour after the completion of the dropping, 39.07 g (0.50 mol) of dimethyl sulfoxide and 6 mL of dichloroethane were added. After another 1 hour, the low boiling material was distilled off, 500 mL of toluene and 500 mL of methanol were added, and the mixture was heated under reflux. After 3 hours, 500 mL of toluene was added to separate the lower layer of the solution and the lower layer was re-extracted once with toluene. The upper layer and the re-extracted toluene were combined and washed once with water, once with 5% layered water, and once with water. 1671.78 g of the desired toluene solution was obtained as an orange liquid.

The title compound in this orange liquid was quantified by gas chromatography (GC quantification). As a result, the GC quantitative yield of the title compound was 79%.

Further, in Synthesis Example 2-3, the generation of white deposits adhering to the inside of the reaction vessel could be suppressed by 95% or more as compared with Synthesis Example 2-1 and Synthesis Example 2-2.

(Synthesis Example 2-4)
After adding 500 mL of dichloroethane and 191.79 g (1.20 mol) of bromine to the flask, heating and stirring in an oil bath until the internal temperature reaches 65 ° C., dimethyl sulfoxide 156 of 18.02 g (0.30 mol) of urea. A 28 g (2.00 mol) solution was added with a dropping funnel. Then, a solution of 283.68 g (purity 99.1%, 1.00 mol) of dimethyl sulfoxide 351.59 g (4.50 mol) of 2'-chloro-4'-(4-chlorophenoxy) acetophenone was added with a dropping funnel. One hour after the completion of the dropping, 39.13 g (0.50 mol) of dimethyl sulfoxide was added. After another 2 hours, the low boiling material was distilled off, 500 mL of toluene and 500 mL of methanol were added, and the mixture was heated under reflux. After 7 hours, the lower layer of the solution was separated and the lower layer was re-extracted once with toluene. The upper layer and the re-extracted toluene were combined and washed with water three times. 261.67 g of a toluene solution of interest was obtained as an orange liquid.

The title compound in this orange liquid was quantified by gas chromatography (GC quantification). As a result, the GC quantitative yield of the title compound was 84%.

<Synthesis example 3>
2- (2-Chloro-4- (4-chlorophenoxy) phenyl) -2-hydroxy-3- (1H-1,2,4-triazole-1-yl) Synthesis of methyl propionate Crude 2- (2- (2-) After adding 152.35 g of methyl chloro-4- (4-chlorophenoxy) phenyl) -2-oxylancarboxylate (purity 74%, 0.33 mol) and 154.12 g of N, N-dimethylacetamide to the flask, 1 , 2,4-Triazole 34.64 g (0.50 mol) and potassium carbonate 23.09 g (0.17 mol) were added, and the mixture was heated and stirred in an oil bath at 50 ° C. After 0.75 hours, the internal temperature was raised to 60 ° C. After 5 hours, the mixture was cooled to room temperature, 111.95 g (equivalent to 0.10 mol) of the reaction solution 363.71 g was transferred to a 500 mL cylindrical separable flask, 50 mL of toluene and 40 mL of water were added, and then the title compound was added. 30 mg of seed crystals were added. After 30 minutes, 160 mL of water was added dropwise and the mixture was stirred at room temperature for 30 minutes, then slowly cooled over 30 minutes using a cyclohexane bath at 6 ° C., and stirring was continued for 3 hours. Then, the crude liquid was suction-filtered and washed with 50 mL of water and 25 mL of toluene. The filtrate was dried under reduced pressure using a vacuum sample dryer to obtain 39.09 g of the desired white solid crude product.

The title compound in this white solid crude product was quantified by high performance liquid chromatography (HPLC quantification). As a result, the HPLC quantitative yield of the title compound was 78%. In addition, triazole-1-yl: triazole-4-yl = 85:15.

36.6 g of the white solid crude product was hot-filtered at 100 ° C. using 164.8 g of toluene while appropriately dividing it. 189 g of the filtrate was added to the flask, the temperature was raised to 100 ° C. in an oil bath, and the mixture was heated and stirred for 10 minutes after the internal temperature reached 100 ° C. After that, it was cooled to 92 ° C. at a rate of 15 ° C./h. After reaching 92 ° C., 159 mg of the seed crystal of the title compound was added, and then stirring was continued at 92 ° C. for 30 minutes. Then, the mixture was cooled at 6 ° C./h up to 75 ° C., 10 ° C./h from 75 ° C. to 55 ° C., and 30 ° C./h from 55 ° C. to 5 ° C., and stirring was continued for 2 hours after reaching 5 ° C. The crude liquid was suction filtered and washed with 11.3 g of cold toluene. The filtrate was dried under reduced pressure using a vacuum sample dryer to obtain 31.2 g of the desired white solid.

The title compound in this white solid crude was quantified (HPLC quantification) by high performance liquid chromatography. As a result, the HPLC quantitative recovery rate of the title compound was 94.6%. At this time, triazole-1-yl: triazole-4-yl = 95: 5.

The powder X-ray diffraction data of the triazole-1-yl form (A), the triazole-4-yl form (B), and the triazole-1-yl: triazole-4-yl = 95: 5 mixture (C) are obtained from germanium. -Recorded at room temperature using CuKα1 irradiation (λ = 1.5406 Å). A 2θ scan was performed at room temperature using a one-dimensional position-sensitive detector between 5 ° ≤ 2θ ≤ 35 ° (step width 0.03 °).

The powder X-ray patterns of the triazole-1-yl compound (A), the triazole-4-yl compound (B) and the triazole-1-yl: triazole-4-yl = 95: 5 mixture (C) are shown in FIG. 1. Shown in 3. Further, the 2θ values of each powder X-ray diffraction pattern are presented in Table 1 below.

The present invention can be used as a method for producing an intermediate for synthesizing an azole derivative useful as a pesticide.

Claims

A method for producing a compound represented by the general formula (IV).

[In formula (IV), R 1 is a C1-C6 - alkyl group;
X 1 is a halogen group, a C1- C4 -haloalkyl group or a C1- C4 -haloalkoxy group;
X 2 is a halogen group, a C1- C4 -haloalkyl group or a C1- C4 -haloalkoxy group;
n is 1, 2 or 3]
In the coexistence of inorganic bases
(A) At least one of dimethyl sulfide and dimethyl sulfoxide, and (b) Methyl-LG (where LG is a nucleophilically replaceable desorbing group, a halogen group, an alkoxysulfonyloxy group, an aryloxysulfonyloxy). Group, alkylsulfonyloxy group, haloalkylsulfonyloxy group, and arylsulfonyloxy group)
The production method comprising the step of converting the compound represented by the general formula (II) into the compound represented by the general formula (IV) using the above:

[In formula (II), R 1 , X 1 , X 2 , and n are identical to R 1 , X 1 , X 2 , and n in formula (IV)].
The production method according to claim 1, wherein in the step of converting to the compound represented by the general formula (IV), the required reaction amounts of the above (a) and (b) are added in divided portions. ..
The production method according to claim 1 or 2, wherein (a) is both dimethyl sulfide and dimethyl sulfoxide.
Further comprising the step of converting the compound represented by the general formula (III) into the compound represented by the general formula (II).
In this step, bromine is allowed to act on the compound represented by the general formula (III) while heating the reaction system in a solvent containing dimethyl sulfoxide, and then R1 - OH (where R1 is represented by the formula (IV)). The production method according to any one of claims 1 to 3, wherein the compound represented by the general formula (II) is produced by the action of (same as R1 in). :

[In formula (III), X 1 , X 2 , and n are the same as X 1 , X 2 , and n in formula (IV)].
In the step of converting to the compound represented by the general formula (II), the reaction system to which bromine is added is heated in a solvent containing dimethyl sulfoxide, and then the compound represented by the general formula (III) is added and generally used. The compound represented by the formula (III) is allowed to act on bromine, and then R1 - OH (where R1 is the same as R1 in the formula (IV)) is allowed to act on the compound represented by the above general formula. The production method according to claim 4, wherein the compound represented by (II) is produced.
The step of converting to the compound represented by the general formula (II) is characterized in that it is carried out in the coexistence of at least one selected from the group consisting of urea, adipic acid dihydrazide and dibutylhydroxytoluene. The manufacturing method according to 4 or 5.
A method for producing a compound represented by the general formula (I).
A method for producing a compound represented by the general formula (IV) according to any one of claims 1 to 6 is included.
The compound represented by the general formula (IV) obtained by the production method, using 1,2,4-triazole in the presence of an inorganic base, is represented by the general formula (I). A manufacturing method comprising a step of converting to:

[In formula (I), R 1 , X 1 , X 2 , and n are the same as R 1 , X 1 , X 2 , and n in formula (IV)].